The cellular components of the BM milieu support multiple myeloma (MM) cell growth, survival, migration and drug resistance, both directly by cell-cell interactions as well as indirectly by production of soluble factors. A key component of this microenvironment is immune cells. During the previous granting period, we have demonstrated antigen specific anti-MM T and B cell responses in patients with monoclonal gammopathy of undetermined significance (MGUS) and MM. Although these responses can affect anti-MM cytotoxicity in vitro, they fail to impede disease progression. While the mechanisms governing tumor-induced immune dysfunction in MM patients are unknown, our preliminary data suggests that tumor cells can inhibit the development of an effective anti-MM immune response. Our preliminary data suggests a number of mechanisms mediating this immune inhibition including: induction of dysfunctional T regulatory cells; ineffective antigen presentation; soluble MICA induced suppression of NKG2D function, and production of excessive pro-inflammatory cytokines associated with NKG2D and TH17 pathways. Based upon these data, we hypothesize that the BM microenvironment modulates the immune responses towards NKG2D dysfunction and TH17 pathways to support tumor progression and inhibit the development of anti-MM immune responses. Our goal in Project 2 is to identify and target cellular and soluble factors modulating autologous anti-MM responses to develop effective strategies tageting these pathways to improve immune responses and inhibit myeloma cell growth. To achieve this goal, we propose the following Specific Aims: to elucidate the role of the NKG2D pathway in MM pathogenesis (Specific Aim 1); to evaluate the role of TH17 pathway and associated pro-inflammatory cytokines in promoting immune dysfunction and tumour growth in MM (Specific Aim 2); to evaluate the role of novel therapies targeting NKG2D and TH17 pathway in vitro and in vivo using animal models as a prelude to future phase I/II clinical trials (Specific Aim 3). These studies will provide the framework to improve immune function and to achieve anti-tumor responses in myeloma.